tbuckley/cabot-search huggingface dataset:
P1233: PRIMARY REFRACTORY PLASMABLASTIC LYMPHOMA: A PRECISION ONCOLOGY APPROACH
Authors: H. Witte, A. Fähnrich, J. Riedl, A. Kuenstner, N. Hertel, N. von Bubnoff, H. Merz, H. Busch, A. Feller, N. Gebauer
Journal: HemaSphere (2022)

Background: The comprehensive implementation of standardized multidisciplinary molecular tumor boards (MTB) and synchronous advancements in genomic profiling diversified the spectrum of treatment strategies in cancer patients, predominantly focusing on those with solid tumors. However, hematologic malignancies remain underrepresented in MTBs. Aims: The current study aimed to assess the potential of precision oncology for primary refractory plasmablastic lymphoma (PBL), a highly lethal blood cancer. Methods: We re-evaluated previously published whole exome sequencing (WES) data of 14 primary refractory PBL cases from initial diagnosis. For this proof-of-concept study, the institutional MTB pipeline (University Cancer Center Schleswig-Holstein: UCCSH) which is certified for routine clinical diagnostics has been conducted for the individual annotation of mutations aiming to virtually recommend molecularly stratified treatment strategies. Evidence levels for MTB-recommendations were defined in accordance with the NCT/DKTK MASTER program. Results: Median age was 76.5 years (range 56-91) and 78.6% patients were male. The composition of given cytoreductive regimens was heterogenous and the overall prognosis was dismal. The standard turn-around time for the MTB pipeline after sampling was 21 days. Potential recommendations on a molecular stratified treatment option with a NCT/DKTK evidence level of at least m2A were detected for each PBL case. Based on immunohistochemical assessment (CD19, CD30, CD38 and CD79B), data-base research revealed targeted treatment recommendations in 11/14 (78.6%) cases. Genetic alterations were classified in accordance with biomarker/treatment baskets proposed by Horak et al. According to baskets, we identified tyrosine kinases (TK; n=7), PI3K-MTOR-AKT pathway (PAM; n=3), cell cycle alterations (CC; n=2), RAF-MEK-ERK cascade (REM; n=2) and others (OTH; n=7) for targeted treatment recommendations. Moreover, immunotherapeutic approaches seemed feasible in 6 PBL cases due to the predominant affection of DNA-damage repair genes. Each recommended drug was either approved by the FDA and/or EMA or at least designated for FDA fast track development. Summary/Conclusion: The presented proof-of-concept study demonstrates the applicability of precision oncology approaches in PBL patients. Due to the aggressive course of the disease, such patients are in urgent medical need for personalized treatment approaches instead of conventional chemotherapeutic options and should be considered for MTB inclusion at the earliest time.
P944: A PHASE I STUDY OF C-CAR088, A NOVEL HUMANIZED ANTI-BCMA CAR T CELL THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
Authors: X. Qu, G. An, W. Sui, T. Wang, X. Zhang, J. Yang, Y. Zhang, L. Zhang, D. Zhu, J. Huang, S. Zhu, X. Yao, J. Li, C. Zheng, S. Chen, K. Zhu, Y. Wei, X. Lv, L. Lan, Y. Yao, D. Zhou, P. Lu, L. Qiu, J. Li
Journal: HemaSphere (2022)

Background: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor-T cell (CAR T) therapy shows remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). Aims: C-CAR088, a novel second-generation humanized anti-BCMA CAR T cell therapy, was developed. Methods: This phase I dose-escalation and expansion study assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM. As of July 2, 2021, 31 patients had been infused with C-CAR088. Results: Any grade cytokine release syndrome (CRS) developed in 29 patients (93.5%), and grade 3 CRS occurred in three patients (9.7%). One patient from the high-dose group (4.5-6.0 × 106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0 × 106 CAR T cells/kg) and high-dose (4.5-6.0 × 106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10-5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR. Summary/Conclusion: Our findings demonstrate the manageable safety profile and potential efficacy of C-CAR088.
Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study
Authors: Beate Schmoele-Thoma, Agnieszka M. Zareba, Qin Jiang, Mohan S. Maddur, Rana Danaf, Alex Mann, Kingsley Eze, Juin Fok-Seang, Golam Kabir, Andrew Catchpole, Daniel A. Scott, Alejandra C. Gurtman, Kathrin U. Jansen, William C. Gruber, Philip R. Dormitzer, Kena A. Swanson
Journal: New England Journal of Medicine (2022)

Although human respiratory syncytial virus (RSV) is an important cause of illness and death in older adults, no RSV vaccine has been licensed.
Biased Study Design and Statistical Analysis in a Need for Intensive Care Unit Admission Surgical Prediction Model
Authors: Roberta Muriel Longo Roepke, Bruno Adler Maccagnan Pinheiro Besen
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
AIO INTEGA Provides Further Support for Immunotherapy in Patients With Advanced <i>ERBB2</i>-Positive Gastroesophageal Adenocarcinoma
Authors: Monica Patel, Nataliya Uboha
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning
Authors: Daniel B. Burkhardt, Beatriz P. San Juan, John G. Lock, Smita Krishnaswamy, Christine L. Chaffer
Journal: Cancer Discovery (2022)

Abstract Phenotypic plasticity describes the ability of cancer cells to undergo dynamic, nongenetic cell state changes that amplify cancer heterogeneity to promote metastasis and therapy evasion. Thus, cancer cells occupy a continuous spectrum of phenotypic states connected by trajectories defining dynamic transitions upon a cancer cell state landscape. With technologies proliferating to systematically record molecular mechanisms at single-cell resolution, we illuminate manifold learning techniques as emerging computational tools to effectively model cell state dynamics in a way that mimics our understanding of the cell state landscape. We anticipate that “state-gating” therapies targeting phenotypic plasticity will limit cancer heterogeneity, metastasis, and therapy resistance. Significance: Nongenetic mechanisms underlying phenotypic plasticity have emerged as significant drivers of tumor heterogeneity, metastasis, and therapy resistance. Herein, we discuss new experimental and computational techniques to define phenotypic plasticity as a scaffold to guide accelerated progress in uncovering new vulnerabilities for therapeutic exploitation.
Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase 3 trial in mantle cell lymphoma
Authors: Simone Ferrero, Daniele Grimaldi, Elisa Genuardi, Daniela Drandi, Gian Maria Zaccaria, Beatrice Alessandria, Marco Ghislieri, Martina Ferrante, Andrea Evangelista, Barbara Mantoan, Gabriele De Luca, Piero Maria Stefani, Fabio Benedetti, Ivana Casaroli, Manuela Zanni, Claudia Castellino, Vincenzo Pavone, Mario Petrini, Francesca Re, Stefan Hohaus, Gerardo Musuraca, Nicola Cascavilla, Chiara Ghiggi, Anna Marina Liberati, Sergio Cortelazzo, Marco Ladetto
Journal: Blood (2022)

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood [PB] and bone marrow [BM]), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression [TTP] hazard ratio [HR], 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/).
P610: SYNERGISTIC ACTIVITY OF FTO INHIBITOR FB23-2 WITH IBRUTINIB IN XENOGRAFT MURINE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: X. Hu, H. Wang, Y. Han, X. Zhang, Z. Tian, Y. Zhang, X. Wang
Journal: HemaSphere (2022)

Background: Several studies have documented that FB23-2, as the selective inhibitor of RNA N6-methyladenosine (m6A) demethylase FTO, exerts crucial role in dampening tumorigenesis. Indeed, FTO deactivation was proved to render resistant leukemia cells sensitive to targeted agents, which suggests a potential combination therapy strategy of FB23-2. Aims: The present study was aimed to identify the synergistic utility of FB23-2 combination with ibrutinib in CLL. Methods: A disseminated leukemia xenograft murine model was established to explore the efficacy of FB23-2 in CLL. Leukemia burden of CLL mice was quantified by luciferase intensity using bioluminescence imaging. Bone marrow and spleen infiltration of leukemic cells was assessed by flow cytometry. And cell survival was determined by cell counting kit-8. Results: To investigate the combinatory effect of FB23-2 and ibrutinib, cell viability assay was performed firstly. FB23-2 displayed potent synergistic activity with ibrutinib in promoting cytotoxicity in CLL cells (Figure 1A). Consistently, FTO silencing mediated by lentivirus exhibited exquisite sensitivity to ibrutinib in CLL cells (Figure 1B). Besides, CLL primary cells and MEC-1 cells with treatment of FB23-2 and ibrutinib simultaneously triggered increased cell apoptosis compared to single agent (Figure 1C). Further underlying cooperative mechanism investigation demonstrated an aberrant activation of DNA damage pathway after serial dilution of FB23-2 treatment. Hence, enhanced expression of p-ATM, p-chk2 and p-H2AX was detected in FTO knockdown and ibrutinib co-treatment group, indicating FTO inhibition inducing ibrutinib-sensitivity via regulating DNA damage (Figure 1D). In addition, we investigated the efficacy of FB23-2 alone and corporation in CLL xenograft murine model. Compared to ibrutinib alone, combination treatment with FB23-2 significantly prolonged the lifespan of CLL mice (median survival time 20 versus 22.5 days, respectively, p=0.02, Figure 1E). FB23-2+ibrutinib group showed an obviously declined proportion of CLL cells compared to ibrutinib-treated alone both in bone marrow(20.93%±2.95% versus 37.17%±4.22%, p=0.02) and spleen (23.58%±6.03% and 54.58%±9.01%, p=0.03, Figure 1F-G). Similar results were obtained with three treated group relative to control group (all p<0.05). Moreover, FB23-2 combined with ibrutinib diminished leukemia burden and splenomegaly in CLL mice (Figure 1H-I). As shown in Figure 1J, leukemia involvement and malignant proliferation were more evident in control group, confirming the potent anti-leukemic activity of FB23-2. Image:Summary/Conclusion: Taken together, our investigation provides pre-clinical evidence for the utility of FB23-2 in CLL, especially combinatory benefit with ibrutinib. FB23-2 represents a promising strategy to novel treatment optimum in CLL.
PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages
Authors: Yukiko Yamaguchi, Jackson Gibson, Kevin Ou, Lupita S Lopez, Rachel H Ng, Neena Leggett, Vanessa D Jonsson, Jelani C Zarif, Peter P Lee, Xiuli Wang, Catalina Martinez, Tanya B Dorff, Stephen J Forman, Saul J Priceman
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163 + M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear. Methods To model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14 + peripheral blood mononuclear cells collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings. Results We observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of programmed death ligand-1 (PD-L1) in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not programmed cell death protein-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163 + M2 macrophages via interferon-γ signaling, resulting in improved antitumor activity of CAR T cells. Conclusion This study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.
Long COVID symptoms in SARS-CoV-2-positive children aged 0–14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study
Authors: Selina Kikkenborg Berg, Pernille Palm, Ulrikka Nygaard, Henning Bundgaard, Maria Nivi Schmidt Petersen, Siri Rosenkilde, Anne Bonde Thorsted, Annette Kjær Ersbøll, Lau Casper Thygesen, Susanne Dam Nielsen, Anne Vinggaard Christensen
Journal: The Lancet Child & Adolescent Health (2022)
Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma
Authors: Andrew X. Zhu, Alexander R. Abbas, Marina Ruiz de Galarreta, Yinghui Guan, Shan Lu, Hartmut Koeppen, Wenjun Zhang, Chih-Hung Hsu, Aiwu Ruth He, Baek-Yeol Ryoo, Thomas Yau, Ahmed O. Kaseb, Adam M. Burgoyne, Farshid Dayyani, Jessica Spahn, Wendy Verret, Richard S. Finn, Han Chong Toh, Amaia Lujambio, Yulei Wang
Journal: Nature Medicine (2022)
A cursory National Food Strategy lacks substance and joined up thinking on food insecurity
Authors: Sabine Goodwin
Journal: BMJ (2022)

In early April 2022, members of the Independent Food Aid Network (IFAN) wrote to Rishi Sunak, the chancellor, and Boris Johnson, the prime minister, to express their "deep concern at the scale of suffering they were already witnessing" as well as their capacity "to prevent people from going hungry in the weeks and months to come." 1 Independent food banks were reaching breaking point.The Food Standards Agency reported that as many as one in six people had used a food bank or food charity in March 2022. 2 And as the number of people being plunged into poverty increases yet further, independent food banks are struggling to cope as food and financial donations plummet. 3Food bank teams have found themselves dipping into charity reserves to source supplies so that no one is turned away.
P1178: BRENTUXIMAB VEDOTIN IN COMBINATION WITH LENALIDOMIDE AND RITUXIMAB IN PATIENTS WITH RELAPSED/REFRACTORY DLBCL: SAFETY AND EFFICACY RESULTS FROM THE SAFETY RUN-IN PERIOD OF THE PHASE 3 ECHELON-3 STUDY
Authors: N. L. Bartlett, C. A. Yasenchak, K. K. Ashraf, W. N. Harwin, J. Orcutt, P. Kuriakose, P. L. Zinzani, A. Mamidipalli, K. Fenton, C. Glenn, G. Nowakowski
Journal: HemaSphere (2022)

Background: Patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after or are ineligible for hematopoietic stem cell transplant (HSCT) or chimeric antigen receptor T cell (CAR-T) therapy generally have poor outcomes. Preclinical data provide the rationale for combining brentuximab vedotin (BV), lenalidomide (len), and rituximab for the treatment of R/R DLBCL. BV+len showed promising clinical activity in a Phase 1 trial with a 57% overall response rate (ORR), 10.2-month median progression-free survival, and 14.3-month overall survival (Ward 2021). Aims: We report the results of the open-label safety run-in that was conducted prior to the randomized portion of the study. Methods: ECHELON-3 (NCT04404283) is a randomized, double-blind, placebo-controlled, active-comparator, multicenter Phase 3 study. Prior to randomization, an open-label safety run-in was conducted; pts received BV (1.2 mg/kg) and rituximab (375 mg/m2) both q3w, and len 20 mg qd. Pts must have received ≥2 prior lines of therapy and be previously treated with or were ineligible for HSCT or CAR-T, ECOG score ≤2, and PET-avid, bidimensional measurable disease (>1.5 cm by CT). Pts with negligible CD30 expression (<1%) were eligible. Response was assessed by the investigator according to the Lugano Classification Revised Staging System (Cheson 2014). Results: 10 pts with R/R DLBCL were enrolled. Median age was 70.5 years, 7 pts were male, and all had an ECOG ≤1. Median prior lines of therapy was 3 (range, 2 to 6); no pts received prior HSCT and 6 pts received prior CAR-T. At a median follow-up of 6.9 months (range, 2.3 to 14.1), the most common treatment emergent adverse events (TEAE) were fatigue (n=5), anemia (n=4) and constipation (n=4). Grade ≥3 events were experienced by 8 pts, most commonly anemia and pneumonia (n=3 each), and neutropenia and thrombocytopenia (n=2 each). Serious adverse events were observed in 7 pts. Seven pts each had BV and rituximab dose modifications, and 6 pts had a len dose modification. The most common reasons for any dose modification were anemia (n=3), neutropenia, peripheral neuropathy, or pneumonia (n=2 each). 4 pts discontinued treatment due to an AE, 2 of which were treatment related (n=1 each of Grade 2 fatigue; Grade 3 anemia). There was 1 death due to a TEAE that was not treatment related. The ORR (best response) was 70%, including 5 pts with a complete metabolic response and 2 pts with a partial metabolic response; 3 pts had progressive disease. Responses were seen in both CD30 (+) and (-) pts, as well as in 4 pts who received prior CAR-T. Summary/Conclusion: This novel triplet regimen appears active in R/R DLBCL with an acceptable safety profile. The randomized portion of the study is currently enrolling.
Combining interventions to reduce the spread of viral misinformation
Authors: Joseph B. Bak-Coleman, Ian Kennedy, Morgan Wack, Andrew Beers, Joseph S. Schafer, Emma S. Spiro, Kate Starbird, Jevin D. West
Journal: Nature Human Behaviour (2022)

Abstract Misinformation online poses a range of threats, from subverting democratic processes to undermining public health measures. Proposed solutions range from encouraging more selective sharing by individuals to removing false content and accounts that create or promote it. Here we provide a framework to evaluate interventions aimed at reducing viral misinformation online both in isolation and when used in combination. We begin by deriving a generative model of viral misinformation spread, inspired by research on infectious disease. By applying this model to a large corpus (10.5 million tweets) of misinformation events that occurred during the 2020 US election, we reveal that commonly proposed interventions are unlikely to be effective in isolation. However, our framework demonstrates that a combined approach can achieve a substantial reduction in the prevalence of misinformation. Our results highlight a practical path forward as misinformation online continues to threaten vaccination efforts, equity and democratic processes around the globe.